1. Field of the Invention
The present invention relates to compositions, unit doses, aerosols, and kits for treating certain heart conditions by pulmonary administration and methods thereof.
2. Background Art
Cardiac arrhythmia (also dysrhythmia) is a term for any of a large and heterogeneous group of conditions in which there is abnormal electrical activity in the heart. The heart beat may be too fast or too slow, and may be regular or irregular.
Atrial arrhythmia is a field with a high level of unmet clinical need. Many drugs used today have been on the market since the early 1980s and 1990s and are mostly inadequate due to either lack of efficacy or a side-effect profile that is primarily cardiac related, that necessitates extensive monitoring of the patient.
What is needed for fast and safe cardioversion (resolution of arrhythmia) is therapy that:
1. Has little to no risk of acceleration of ventricular rate before cardioversion;
2. Slows atrio-ventribular (AV) conduction so that there is rate control and cardioversion at the same time;
3. Has little to no effect in prolonging the QRS interval and should have a low risk of torsade de pointes; and
4. Has little to no negative inotropic effect; it should have only mild negative chronotropic effect, without the risk of severe bradycardia when the patient reverts to sinus rhythm.
None of the current approved drug products exhibit these characteristics. High oral and intravenous (IV) doses required to compensate for absorption, metabolism, and dilution result in blood high blood concentrations for an extended period of time that cause the dangerous adverse cardiac events like pro-arrhythmias, QT prolongation, and torsade de pointes. FELDMAN et al., “Analysis of Coronary Response to Various Doses of Intracoronary Nitroglycerin,” Circulation, 66:321-327 (1982); and BARBATO et al., “Adrenergic Receptors in Human Atherosclerotic Coronary Arteries,” Circulation, 111:288-294 (2005). Comorbid conditions also limit use of ideal drugs in some patients, for example the case with intravenous adenosine. GAGLIONE et al., “Is There Coronary Vasoconstriction after Intracoronary Beta-adrenergic Blockade in Patients with Coronary Artery Disease,” J Am Coll Cardiol, 10:299-310 (1987). Drugs like verapamil and diltiazem injections are second line of therapy requiring close monitoring of patients. NOGUCHI et al., “Effects of Intracoronary Propranolol on Coronary Blood Flow and Regional Myocardial Function in Dogs,” Eur J Pharmacol., 144(2):201-10 (1987); and ZALEWSKI et al., “Myocardial Protection during Transient Coronary Artery Occlusion in Man: Beneficial Effects of Regional Beta-adrenergic Blockade,” Circulation, 73:734-73 (1986).
Paroxysmal atrial fibrillation (PAF) is a subset of the overall atrial fibrillation (AF) population and is estimated to be 25-30% of the overall AF population. About 2.5 million patients are affected by AF in the United States. The population of PAF patients is estimated to be 900,000 to 1.5 million worldwide.
Paroxysmal supraventricular tachycardia (PSVT) is an arrhythmia that affects younger and healthy populations who are active (e.g., athletes). About 500,000 to 600,000 patients have PSVT in the United States.
Ablation techniques, e.g., RF ablation, are often used to treat arrhythmias. But ablation is expensive with the cost typically ranging from about $25,000 to $36,000 per procedure. Despite the high expense, ablation may not completely correct the arrhythmia. Often, multiple ablation procedures are required to achieve a satisfactory result.
Oral medications, e.g., pills, tend to require high doses and time for onset of action. The oral dose for heart medications generally tends to be well over 1 mg. High doses increase the likelihood of side effects and drug-drug interactions as these patients typically take multiple medications. The time for onset for oral cardiovascular medications tends to be around 60 minutes. Oral antiarrhythmic medications have been predominantly developed for prevention with treatment being given intravenously.
Intravenous injection usually requires a hospital environment for administering a medicine and typically involves a visit to the emergency room (ER). These overheads result in this therapy being expensive compared to therapies where the patients can self-administer their medicines. Intravenous injection requires a dose that is higher than what is actually needed in the heart to compensate for dilution and metabolism. Drug injected by IV passes through the right side of the heart and then the lungs before reaching the left side of the heart. See FIG. 1. The drug remains in the blood stream at a high concentration bathing all the organs and tissues with this drug in a high concentration, until the drug gets excreted through the kidneys or through other metabolic routes (e.g., hepatic). As a result, IV drugs may cause unwanted side effects. Drugs administered via the IV route are significantly diluted in the venous blood volume and lungs before reaching the cardiac circulation.
Injecting the heart directly is usually a last-resort taken by a cardiologist as a life saving measure in an emergency. The doses of the drugs injected directly into the heart in this manner are usually less than their IV and/or oral doses.
In some cases, an unplanned surgery is necessary to save the patient's life. Of course, unplanned surgeries are expensive and risky to the patient.
Cardiac arrhythmias are associated with disabling symptoms like tightness around the chest, palpitations, feeling tired, and sometimes chest pain.
In view of the above, arrhythmias frequently result in emergency room (ER) visits, where intravenous drugs are administered, sometimes necessitating an extended stay in the hospital and in some cases also leading to unplanned invasive procedures. Pipeline Insights: Antiarrhythmics, Datamonitor (June 2006); and TWISS et al., “Efficacy of Calcium Channel Blockers as Maintenance Therapy for Asthma,” British J of Clinical Pharmacology (November 2001).
There remains, however, a need for improved compositions and methods for treating heart conditions. Accordingly, there also remains a need for methods of making these compositions.